The present invention relates to novel antiobesity and hypocholesterolemic compounds, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids of the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereosomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. 
The present invention also relates to a process for the preparation of the above said novel compounds, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, novel intermediates and pharmaceutical compositions containing them.
The compounds of the present invention lower total cholesterol CC); increase high density lipoprotein HL) and decrease low density lipoprotein (LDL), which have beneficial effect on coronary heart disease and atherosclerosis.
The compounds of general formula (I) are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders"". These compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, lowering of atherogenic lipoproteins, very low density lipoprotein (VLDL) and LDL. The compounds of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, retinopathy, and nephropathy The compounds of general formula (I) are also useful for the treatment/prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease, and other cardiovascular disorders. These compounds may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, xanthoma and for the treatment of cancer. The compounds of the present invention are useful in the treatment and/or prophylaxis of the above said diseases in combination/concomittant with one or more HMG CoA reductase inhibitors or hypolipidemic/hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol.
Atherosclerosis and other peripheral vascular diseases are the major causes effect the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and the development of effective therapeutic strategies.
Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called xe2x80x9cnormalxe2x80x9d level. Recently, it has been accepted that xe2x80x9cidealxe2x80x9d plasma levels of cholesterol are much below the xe2x80x9cnormalxe2x80x9d level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the xe2x80x9coptimumxe2x80x9d (or xe2x80x9cidealxe2x80x9d) value. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as low density lipoprotein (LDL), intermediate density lipoprotein (IDL), high density lipoprotein (HDL) and partially as very low density lipoprotein (VLDL). Studies clearly indicate that there is an inverse correlationship between CAD and atherosclerosis with serum HDL-cholesterol concentrations. (Stampfer et al., N. Engl. J. Med., 325 (1991), 373-381) and the risk of CAD increases with increasing levels of LDL and VLDL.
In CAD, generally xe2x80x9cfatty streaksxe2x80x9d in carotid, coronary and cerebral arteries, are found which are primarily free and esterified cholesterol. Miller et al., (Br. Med; J., 282 (1981), 1741-1744) have shown that increase in HDL-particles may decrease the number of sites of stenosis in coronary arteries of humans, and high level of HDL-cholesterol may protect against the progression of atherosclerosis. Picardo et al., (Arteriosclerosis 6 (1986) 434-441) have shown by in vitro experiment that HDL is capable of removing cholesterol from cells. They suggest that HDL may deplete tissues of excess free cholesterol and transfer them to the liver (Macikinnon et al., J. Biol. Chem. 261 (1986), 2548-2552). Therefore, agents that increase HDL cholesterol would have therapeutic significance for the treatment of hypercholesterolemia and coronary heart diseases (CHD).
Obesity is a disease highly prevalent in affluent societies and in the developing world and which is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression has been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems.
Diabetes and insulin resistance is yet another disease which severely effects the quality of life of a large population in the world. In insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes. Among the developed countries, diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyperlipidemia (J. Clin. Invest., (1985) 75: 809-817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66: 580-583; J. Clin. Invest., (1975) 68: 957-969) and other renal complications (See Patent Application No. WO 95/21608). It is now increasingly being recognized that insulin resistance and relative hyperinsulinemia have a contributory role in obesity, hypertension, atherosclerosis and type 2 diabetes mellitus. The association of insulin resistance with obesity, hypertension and angina has been described as a syndrome having insulin resistance as the central pathogenic link-Syndrome-X.
Hyperlipidemia is the primary cause of cardiovascular (CVD) and other peripheral vascular diseases. High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and VLDL (Very Low Density Lipoprotein) seen in hyperlipidemia. Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD. Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
Peroxisome proliferator activated receptors (PPAR) are members of the nuclear receptor super family. The gamma (xcex3) isoform of PPAR (PPARxcex3) has been implicated in regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha (xcex1) isoform of PPAR (PPARxcex1) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol. (1995) 5: 618-621). PPARxcex1 agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that the hypolipidaemic effect is enhanced when the molecule has both PPARxcex1 and PPARxcex3 agonist activity and are suggested to be useful for the treatment of syndrome X (WO 97/25042). Synergism between the insulin sensitizer (PPARxcex3 agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma (EP 0 753 298).
It is known that PPARxcex3 plays an important role in adipocyte differentiation (Cell, (1996) 87, 377-389). Ligand activation of PPAR is sufficient to cause complete terminal differentiation (Cell, (1994) 79, 1147-1156) including cell cycle withdrawal. PPARxcex3 is consistently expressed in certain cells and activation of this nuclear receptor with PPARxcex3 agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997) 94, 237-241) and inhibition of cancer expression of prostate cancer tissue (Cancer Research (1998) 58, 3344-3352). This would be useful in the treatment of certain types of cancer, which expresses PPARxcex3 and could leading to a quite nontoxic chemotherapy.
Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications. Kallen et al (Proc. Natl. Acad. Sci., (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to their PPAR agonist expression and therefore lower plasm leptin concentrations. However, it has been recently disclosed that compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO 98/02159).
A few xcex2-aryl-xcex1-hydroxy propionic acids, their derivatives, and their analogs have been reported to be useful in the treatment of hyperglycemia and hypercholesterolemia. Some of such compounds described in the prior art are outlined below:
i) U.S. Pat. No. 5,306,726; and WO 91/19702 disclose several 3-aryl-2-hydroxy-propionic acid derivatives of general formula (II a) and (II b) as hypolipidemic and hypoglycemic agents. 
Examples of these compounds are shown in formula (II c) and (II d) 
ii) International Patent Applications, WO 95103038 and WO 96104260 disclose compounds of formula (II e) 
xe2x80x83wherein Ra represents 2-benzoxazolyl or 2-pyridyl and Rb represents CF3, CH2OCH3 or CH3. A typical example is (S)-3-[4-[2[-N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(2,2,2-trifluoroethoxy)propanoic acid (II f). 
iii) International Patent Application Nos. WO 94/13650, WO 94/01420 and WO 5/17394 disclose the compounds of general formula (II g)
A1xe2x80x94Xxe2x80x94(CH2)nxe2x80x94Oxe2x80x94A2xe2x80x94A3xe2x80x94Y.R2 xe2x80x83xe2x80x83(II g) 
xe2x80x83wherein A1 represent aromatic heterocycle, A2 represents substituted benzene ring and A3 represents moiety of formula (CH2)mxe2x80x94CHxe2x80x94(OR1), wherein R1 represents alkyl groups, m is an integer of the range of 1-5; X represents substituted or unsubstituted N; and Y represents Cxe2x95x90O or Cxe2x95x90S. R2 represents OR3 where R3 may be hydrogen, alkyl, aralkyl, or aryl group; and n represents an integer in the range of 2-6. An example of these compounds is shown in formula (II h) 
With an objective to develop novel compounds for lowering cholesterol and reducing body weight with beneficial effects in the treatment and/or prophylaxis of diseases related to increased levels of lipids, atherosclerosis, coronary artery diseases, Syndrome-X, impaired glucose tolerance, insulin resistance, insulin resistance leading to type 2 diabetes and diabetic complications thereof, for the treatment of diseases wherein insulin resistance is the patho-physiological mechanism, for the treatment and/or prophylaxis of leptin resistance and complications thereof, hypertension, atherosclerosis and coronary artery diseases with better efficacy, potency and lower toxicity, we focussed our research to develop new compounds effective in the treatment of above mentioned diseases. Effort in this direction has led to compounds having general formula (I).
The main objective of the present invention is therefore, to provide novel xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates and pharmaceutical compositions containing them, or their mixtures.
Another objective of the present invention is to provide novel xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPARxcex1 and/or PPARxcex3, and or unsubstituted or substitutedinhibit HMG CoA reductase, in addition to agonist activity against PPARxcex1 and/or PPARxcex3.
Another objective of the present invention is to provide novel xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
Yet another objective of the present invention is to produce a process for the preparation of novel xcex2-aryl-xcex1-oxysubstituted alkylcarboxylic acids of the formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates.
Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of the general formula (I), their analogs, their derivatives, their tautomers, their stereoisomers, their polymorphs, their salts, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
Another objective of the present invention is to provide novel intermediates, a process for their preparation and use of the intermediates in processes for preparation of xcex2-aryl-xcex1-oxysubstituted alkyl carboxylic acids of formula (I), their derivatives, their analogs, their tautomers, their stereoisomers, their polymorphs, their salts and their pharmaceutically acceptable solvates.